The anti-lung cancer activity of propylene tethered dihydroartemisinin-isatin hybrids

Nineteen propylene tethered dihydroartemisinin-isatin hybrids 5a-g and 6a-l were designed, synthesized, and screened for their in vitro antiproliferative activity against three lung cancer cell lines, inclusive of drug-sensitive (A549), doxorubicin-resistant A549 (A549/DOX) and cisplatin-resistant A549 (A549/DDP) cell lines. The cytotoxicity of the synthesized hybrids towards normal lung epithelial cell line (BEAS-2B) was also assessed to evaluate the selectivity. The structure-activity relationship (SAR) elucidated that (1) alkyloxylimino fragment at C-3 position of isatin moiety were more favorable than the carbonyl and benzoxylimino, and the relative contri-cution order was methoxylimino > ethoxylimino > carbonyl > benzoxylimino; halogen atom at C-5 or C-6 position of isatin fragment could enhance the activity. Among them, hybrid 6f (IC50: 21.7-28.9 mu M) showed promising activity against the three tested lung cancer cell lines, and the activity was not inferior to that of cisplatin (IC50: 19.7 and 66.9 mu M) and doxorubicin (IC50: 54.3 and 15.1 mu M) against multidrug-resistant A549/DOX and A549/DDP lung cancer cell lines. In addition, hybrid 6f (IC50: > 100 mu M) was non-cytotoxic towards normal lung epithelial cell line (BEAS-2B), and the RI values of hybrid 6f were 1.12 and 1.33. Further, hybrid 6f also possessed acceptable stability in mouse and human microsomes. Accordingly, hybrid 6a was a promising anti-lung cancer chemotherapeutic candidate and merited further evaluations.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Automated summary

A series of propylene tethered compounds were designed and synthesized, and their antiproliferative activity against lung cancer cell lines was evaluated. Among them, hybrid 6f showed promising activity against drug-resistant lung cancer cells and low cytotoxicity towards normal lung cells. It also exhibited acceptable stability in vitro and in vivo.